This invention relates generally to an apparatus and method for eliminating viruses by means of extracorporeal whole body hyperthermia, and more particularly to an apparatus and method that regulates the blood pH, pCO2, and base excess, thereby maintaining a constant CO2 as the patients body temperature is increased.
The use of heat to treat ailments dates back many centuries to ancient Egyptian times, where certain cancers were treated by partial burial of the patient in hot sand. The use of hyperthermia as a treatment has continued into the twentieth century. Hyperthermia presents a unique set of physiologic problems that require careful management in order to achieve success. These problems have plagued soldiers on the battlefield, inner city residents during heat waves, and clinicians trying to treat cancer and AIDS.
In homoiothermal bodies, thermoregulation and maintenance of near normal temperature automatically takes precedence over other homeostatic functions, including electrolyte balance. In order to maintain normal temperatures during external exposure to heat, the body responds through an increase in both cardiac output, and more importantly, respiratory rate well above metabolic needs, thereby ridding the body of excess heat. The bulk of the blood is directed to the cutaneous vessels of the skin through increased cardiac output, while the increase respiratory rate or hyper ventilatory response is akin to the panting of a dog. A negative consequence of hyperventilation is that an increased respiratory rate effectively and drastically reduces the pCO2 (and total CO2) of the circulating blood creating a respiratory alkalosis. This decrease in pCO2 increases the pH gradient across the cellular membrane. To regain electrical neutrality between intra and extracellular compartments there is a shift of ions between these two spaces, many of which may be lost due to renal excretion. Additionally, cellular function may be impaired as enzyme activity is adversely affected by electrolyte imbalance.
The measurement of intracellular pH has only been reliably performed within the last 25 to 30 years, therefore, most of this knowledge had gone unnoticed until 15 years ago. Researchers studying better methods of myocardial protection during hypthermic/cardioplegia cardiac arrest discovered that alkalotic infusion into the coronary arteries prior to the removal of the aortic cross clamp prevented the so called reperfusion injury.
During normal arterial blood flow, at 37xc2x0 C. the arterial pH is approximately 7.4, having an arterial carbon dioxide tension of about 40 torr (mmHg). The human body modulates the arterial pCO2 levels as temperature and the CO2 content in the blood are altered. It is known that during hypothermic reactions, when the body temperature is decreased, there is a decrease in pCO2 due to increased solubility, and increases in the blood pH. Generally, the xcex94pH/xc2x0 C.≅xe2x88x920.015 when the CO2 content of blood and the [OHxe2x88x92]/[H+] remain constant. Also, pN is defined as the pH of the neutrality of water where [H+]+[OHxe2x88x92]=1, that is when ionic balance is achieved. This balance is governed by the ionization constant of water Kw and varies with temperature. As temperature rises the pN is reduced. Of the three known buffer systems, it is believed that imidazole moiety of a person""s blood accounts for this relationship.
Researchers in whole body hyperthermia have used temperature correction of blood gases (pH-stat). During the use of pH-stat, researches have observed electrolyte replacement and metabolic acidosis even with a reduced Axe2x80x94V O2 difference. One explanation for this is that the use of the pH-stat technique artificially imposes a respiratory alkalosis which in turn affects oxyhemoglobin dissociation, reducing the availability of oxygen to the tissue.
In studies of heterotherms, or cold blooded animals, it was noted that as they were exposed and equilibrated to different temperatures, the pCO2 values varied as the temperature dependent solubility factor changed, without concomitant alteration of total CO2 content, which in turn resulted in an inverse change in pH. The misconception of homoiotherm (warm blooded) blood gas regulation insists that normality is based upon the blood pH of 7.40 and a pCO2 of 40 torr and that changes of temperature do not effect this relationship. Indeed, pioneering work in cardiovascular surgery studied the effects of hypothermia on hibernating animals which maintain those values at lowered temperature. However, in the latter case hormonal and central nervous system intervention has affected the organism in ways which are not yet completely understood. In any case it is not the pH of the blood that is important, it is that of the intracellular space where the chemical reactions of life takes place.
Alpha-stat blood gas management achieved better methods of myocardial protection and was proposed for use during open heart surgery. Later, it was discovered that alpha-stat preserved the mechanisms of cerebral autoregulation, i.e. the appropriate blood flow rate for the metabolic needs of the brain. The practice of adding CO2 to the blood in the oxygenator to maintain a normal temperature corrected pCO2 (pH-stat) resulted in a blood flow exceeding demand as the pCO2 is the controlling factor of cerebral autoregulation. The use of pH-stat regulation during hypothermic treatments produces a notable decrease in plasma phosphorous concentrations. Alternatively, the use of alpha-stat during total body hypothermia, reduces the amount of reduction in plasma phosphorous concentrations. The fact that alpha-stat may have an overall beneficial effect on human physiology, during hyperthermia, has largely gone unnoticed.
The properties of imidazole moiety of protein-bound histidine is described by White et al. in a paper entitled xe2x80x9cCarbon Dioxide Transport and Acid-Base Balance During Hypothermiaxe2x80x9d (Pathophysiology and Techniques of Cardiopulmonary Bypass, 1983; Vol. II: 40-48). White et al. states that imidazole moiety is present in a persons blood in sufficient quantity to account for the pH-temperature relationship. The state of protonization (charged state) of imidazole is expressed as a variable (alpha) equal to the ratio of deprotonated to total imidazole groups. White et al. notes that the maintenance of a constant alpha, referred to as alpha-star  alpha-stat behavior, occurs when carbon dioxide partial pressure (pCO2) is appropriately regulated by ventilation. During a decrease in temperature (hypothermia), the maintenance of arterial blood at constant CO2 content is achieved either by reducing the base excess of the blood or elevating pCO2 as a function of temperature. Claude B. Kancir and Tommy Madsen in an article entitled Effect of Acid-Base Management With or Without Carbon Dioxide on Plasma Phosphate Concentration During And After Hypothermic Cardiopulmonary Bypass; Scand J Thor Cardiovasc Surg. 151-155, 1992, concluded that xe2x80x9cacid-base management may influence phosphate homeostasis during hypothermia for cardiac surgery.xe2x80x9d
As recognized in Sites et al. U.S. Pat. No. 5,391,142, hyperthermic treatment of a patient""s blood has been well accepted as a cancer treatment. Sites et al. recognized that the hyperthermic treatment of blood could be used to treat for cancer, acquired immune deficiency syndrome (AIDS), collagen vascular diseases such as rheumatoid arthritis and scleroderma, hepatitis, and Epstein-Barr virus. Sites et al. did not, however, recognize the need to regulate the biochemical reactions fundamental to the metabolic welfare of the organisms within a patient""s blood while the viruses within the patient""s blood are eliminated.
During hyperthermia, pCO2 varies directly with a change in body temperature. It is desirous to hold the bloods CO2 content constant during alpha-stat regulation, thereby requiring an inverse relationship between air convection requirements and body temperature. Alpha-star  Alpha-stat maintains constant CO2 by regulating pCO2. Hence, utilizing the alpha-stat technique for blood gas-management is advantageous in that the pH gradient across the cellular membrane is preserved throughout the range of temperatures encountered during hyperthermia.
The present invention includes an apparatus and method for use in performing extracorporeal whole body hyperthermia maintaining a constant CO2 content by regulating the pH, pCO2, and base excess of the blood. The apparatus and method consolidate and coordinate components used in treatments. They, thereby, address many of the dictates and solve many of the problems of the related art.
The problems alluded to above are solved in accordance with the present invention by providing an apparatus and method for extracorporeal hyperthermic treatment of a patient""s blood. By direct control of pulmonary ventilation through manipulation of respiratory rate, the pCO2, the total CO2, and the pH can be maintained throughout the procedure according to alpha-stat parameters, ensuring that electrolyte balance is maintained throughout. In a recent clinical trial of 6 AIDS patients at 41xc2x0 to 42xc2x0 C. for up to 220 min., this technique was implemented with outstanding results. No electrolyte replacement was required in any patient during the procedure, nor was there ever a need to administer sodium bicarbonate for metabolic acidosis.
The apparatus of the present invention consists of a blood flow circuit which is cannulated to the patient. The blood flow circuit comprises several noncontinuous conduits coupled in series to the following: a Blood Gas Analyzer (BGA) or probes connected to a BGA, pump, pressure transducer, heat exchanger, temperature probe, filter, flow probe, and clamps. If desired, the entire flow circuit could be a disposable unit, whereby a medical treatment facility could inhibit the possibility of contamination of the blood of one patient by the blood of another patient previously treated (cross-contamination). A blood flow circuit, similar to the blood flow circuit described by Sites et al. in U.S. Pat. No. 5,391,142 may be used, the description of which is incorporated herein by reference.
A motor which drives the pump is coupled physically to the pump and electrically to a microprocessor. The microprocessor controls the speed of the motor and consequently the rate the blood is pumped through the flow circuit. The BGA may be linked to the microprocessor or may be a stand alone unit. The microprocessor is also connected to the heat exchanger, thereby allowing the operator to vary the temperature of the blood. Leads from the temperature probe, flow probe, and pressure transducer are connected to an analog/digital converter which is coupled to the microprocessor. The microprocessor utilizes the information from the probes, transducer and BGA is controlling the motor and heat exchanger.
Within the BGA is an analyzer which analyzes the blood gases, including the blood pH and pCO2 through infra-red or chemical analysis. A pulse oximeter attached to the patient through suitable means, measures the pO2 of a patient""s blood. The microprocessor then analyzes the data associated with the blood""s pH, pCO2, pO2 and calculates the base excess of the blood normalized at 37xc2x0 C. The microprocessor is programmed to then automatically adjust the respiratory rate of the patient and either the amount of NaHCO3 or acidotic crystalloid solution (which affects the HCO3xe2x88x92 ion concentration) being introduced into the patient""s blood. This may be accomplished by adjusting the respiratory rate of the patient through ventilation or medications.
The respiratory management of the blood at constant CO2 content, while the temperature is changed, maintains a constant alpha thereby stabilizing the biochemical reactions fundamental to the metabolic welfare of organisms within the patient""s blood. The sodium bicarbonate buffering system is based upon the following equation:
H++HCO3xe2x88x92xcx9cH2CO3xcx9cH2O+CO2 
Acidosis (↓pH) occurs when there is an increase of H+ (metabolic) and/or CO2 (respiratory). Respiratory acidosis is treated with changes in depth of ventilation or ventilatory rate. Metabolic acidosis is treated with the administration of sodium bicarbonate (NaHCO3). xe2x80x9cBicarbxe2x80x9d dissociates into Na+ and HCO3xe2x88x92 which combines with H+ to form CO2 and H2O.
The blood gases, pH, pO2, pCO2, and HCO3xe2x88x92 concentration are obtained by direct measurement. Base excess (BE) is a derived parameter based upon the relationship between the measured pCO2, and HCO3xe2x88x92 concentration, and is calculated relative to the normal HCO3xe2x88x92 concentration values: 24 mEq/L in arterial blood and 26 mEq/L in venous blood.
It is accordingly a principal object of the present invention to remove viruses from a patient""s blood through extracorporeal hyperthermia while regulating the acid-base equilibrium of the patient""s blood as the patient""s body temperature is changed.
Another object of the present invention is to provide a method of treating the patient""s blood during extracorporeal hyperthermic treatment, whereby, the biochemical reactions fundamental to the metabolic welfare of the organisms in a patient""s blood is stabilized.
Yet another object of the present invention is to provide an economical apparatus for the hyperthermic treatment of blood which regulates the patients blood to keep the acid-base equilibrium of the blood constant, wherein all components in contact with the patient""s blood are disposable.
These and other objects and advantages as well as these and other features will become apparent to those skilled in the art from the following detailed description of a preferred embodiment of the invention, especially when considered in conjunction with the accompanying drawings in which like numerals in the several view refer to corresponding parts.